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Nitric oxide (NO) production is critical for the host defense against intracellular pathogens; however, it is unclear whether NO-dependent control of intracellular organisms depends on cell-intrinsic or cell-extrinsic activity of NO. For example, NO production by infected phagocytes may enable these cells to individually control their pathogen burden. Alternatively, the ability of NO to diffuse across cell membranes might be critical for infection control. Here, using a murine ear infection model, we found that, during infection with the intracellular parasite Leishmania major, expression of inducible NO synthase does not confer a cell-intrinsic ability to lower parasite content. We demonstrated that the diffusion of NO promotes equally effective parasite killing in NO-producing and bystander cells. Importantly, the collective production of NO by numerous phagocytes was necessary to reach an effective antimicrobial activity. We propose that, in contrast to a cell-autonomous mode of pathogen control, this cooperative mechanism generates an antimicrobial milieu that provides the basis for pathogen containment at the tissue level.

BackgroundPrevious studies have shown associations between the use of anticholinergics (AC) and cognitive performance in the elderly, considering AC as a homogeneous set of drugs. The present study aims to assess the relationship between exposure to AC drugs and cognitive performance in middle-aged adults according to AC potency and drug class.MethodsOur cross-sectional study used baseline data of 34 267 participants aged 45–70 from the Consultants des centres d’examen de santé de la sécurité sociale (CONSTANCES) cohort. The cumulative exposure to AC was measured using national reimbursement databases over the 3-year period preceding assessment of cognitive performance. Eight classes of AC drugs were differentiated. Episodic verbal memory, language abilities and executive functions were evaluated by validated neuropsychological tests. Analyses were controlled on lifestyle and health status variables.ResultsThis study showed a negative association between overall cumulative AC exposure and cognitive performances after adjustment. The use of drugs with possible AC effect according to the Anticholinergic Cognitive Burden scale (ACB-1 score) was only associated with executive functions. Analyses of AC exposure across drug classes showed a negative association between the use of AC antipsychotics and all cognitive functions assessed. Heterogeneous associations were found for the use of AC anxiolytics, AC opioids and AC drugs targeting the gastrointestinal tract or metabolism. We did not find significant associations between the use of antihistamines, antidepressants, cardiovascular system or other AC medications and cognitive function.ConclusionAssociation between AC drugs and cognitive performance was highly heterogeneous across drug classes; this heterogeneity will have to be considered by future studies.

BackgroundDuring past outbreaks of Ebola virus disease (EVD) and other infectious diseases, health service utilisation declined among the general public, delaying health seeking behaviour and affecting population health. From May to July 2018, the Democratic Republic of Congo experienced an outbreak of EVD in Equateur province. The Ministry of Public Health introduced a free care policy (FCP) in both affected and neighbouring health zones. We evaluated the impact of this policy on health service utilisation.MethodsUsing monthly data from the national Health Management Information System from January 2017 to January 2019, we examined rates of the use of nine health services at primary health facilities: total visits; first and fourth antenatal care visits; institutional deliveries; postnatal care visits; diphtheria, pertussis and tetanus (DTP) vaccinations and visits for uncomplicated malaria, pneumonia and diarrhoea. We used controlled interrupted time series analysis with a mixed effects model to estimate changes in the rates of services use during the policy (June–September 2018) and afterwards.FindingsOverall, use of most services increased compared to control health zones, including EVD affected areas. Total visits and visits for pneumonia and diarrhoea initially increased more than two-fold relative to the control areas (p<0.001), while institutional deliveries and first antenatal care increased between 20% and 50% (p<0.01). Visits for DTP, fourth antenatal care visits and postnatal care visits were not significantly affected. During the FCP period, visit rates followed a downward trend. Most increases did not persist after the policy ended.InterpretationThe FCP was effective at rapidly increasing the use of some health services both EVD affected and not affected health zones, but this effect was not sustained post FCP. Such policies may mitigate the adverse impact of infectious disease outbreaks on population health.

Objectives. To examine whether stressful job exposure to the public could be associated with having long-term benzodiazepine use. Methods. From the participants included between 2012 and 2016 in the French population-based CONSTANCES cohort, 13 934 men and 19 261 women declared a daily job exposure to the public and rated the frequency of stressful exposure. We examined benzodiazepine long-term use by using drug reimbursement administrative registries. Logistic regressions provided odds ratios (ORs) of benzodiazepine long-term use, with stratification for gender and adjustment for age, education, and area deprivation index. Occupational grade, job strain, depression, self-rated health, and alcohol use disorder were additional stratification variables. Results. Benzodiazepine long-term use was positively associated with stressful exposure to the public (“often or always” vs “rarely or never”) in men (OR = 2.2; 95% confidence interval [CI] = 1.8, 2.8) and women (OR = 1.6; 95% CI = 1.4, 1.9), with dose-dependent relationships (P trends < .001). Adjustments and analyses in subgroups without other individual or environmental vulnerability factors led to similar results. Conclusions. Stressful job exposure to the public increases the risk of benzodiazepine long-term use. Prevention programs aiming at reducing the burden of benzodiazepine long-term use would benefit in targeting this specific population.